CN103772311B - 2, the 2- dimethylthiazoles alkyl compound and its preparation method and purposes of substitution - Google Patents
2, the 2- dimethylthiazoles alkyl compound and its preparation method and purposes of substitution Download PDFInfo
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- 238000006467 substitution reaction Methods 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 230000011132 hemopoiesis Effects 0.000 claims abstract description 10
- 210000000987 Immune System Anatomy 0.000 claims abstract description 7
- 239000011780 sodium chloride Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- FDPIMTJIUBPUKL-UHFFFAOYSA-N 3-Pentanone Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 5
- 229940079593 drugs Drugs 0.000 claims description 5
- OGYGFUAIIOPWQD-UHFFFAOYSA-N Thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-Methyl-2-butene Chemical class CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 230000003537 radioprotector Effects 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 5
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 3
- 125000001424 substituent group Chemical group 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 210000002808 Connective Tissue Anatomy 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 239000003102 growth factor Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- -1 2,2- dimethylthiazoles alkane Chemical class 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 210000000952 Spleen Anatomy 0.000 description 6
- 210000001541 Thymus Gland Anatomy 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 210000000265 Leukocytes Anatomy 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 210000003229 CMP Anatomy 0.000 description 4
- 230000035492 administration Effects 0.000 description 4
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001649 bromium compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000002496 gastric Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 210000000683 Abdominal Cavity Anatomy 0.000 description 2
- JKOQGQFVAUAYPM-UHFFFAOYSA-N Amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 2
- 229960001097 Amifostine Drugs 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 210000004027 cells Anatomy 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JVDWKJQBWSKJOJ-UHFFFAOYSA-N 1-bromo-3-methylbuta-1,3-diene Chemical class CC(=C)C=CBr JVDWKJQBWSKJOJ-UHFFFAOYSA-N 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N Allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 206010002855 Anxiety Diseases 0.000 description 1
- 206010057666 Anxiety disease Diseases 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- 210000001185 Bone Marrow Anatomy 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical class ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 229960002433 Cysteine Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- JTEJPPKMYBDEMY-UHFFFAOYSA-N O-methylserotonin Chemical class COC1=CC=C2NC=C(CCN)C2=C1 JTEJPPKMYBDEMY-UHFFFAOYSA-N 0.000 description 1
- 229910004727 OSO3H Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001262 acyl bromides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002607 hemopoietic Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000006178 methyl benzyl group Chemical group 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N γ-Hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to substituted 2,2 dimethylthiazole alkyl compounds and its preparation method and application.The compound of the logical formula (I) of open request protection specifically of the present inventionWherein R is selected from C1‑C6Straight chain and the preferred pi-allyl of the undersaturated alkyl substituent of branch, isopentene group, 2 alkenyl of fourth or aromatic radical and the preferred benzyl of substituted aromatic group and substituted benzyl, can also be C1‑C6Straight chain and branch carbonyl substituent group, the wherein carbonyl substitution collection can also be by the substituent group containing heteroaromatic, the 49-Phe ,82-Ser,115-Arg,144-Met,145-Asn ,161-Arg,169-Met Human Connective tissue growth factors containing sulfydryl.And its pharmaceutically acceptable salt, the Pharmaceutical composition including noval chemical compound and its purposes in radiation protection and protection hematopoiesis and immune system.
Description
Technical field
The present invention relates to a kind of novel substituted 2,2- dimethylthiazole alkyl compounds, its preparation method and its
Protect hematopoiesis, immune system, the purposes in radiation protection.
Background technology
Ionising radiation (X or gamma-rays, the neutron and α particles with enough energy) makes biological tissue generate activity freely
Base, these free radicals and critical macromolecular such as DNA, protein or biological membrane interaction, cause cellular damage or even can
It can cause cell dysfunction and apoptosis.In recent years, with the anxiety of world's nuclear safety situation and the rapid hair of radiotherapy
After nuclear leakage accident occurs for exhibition, especially Fukushima, Japan nuclear power station, the research of radioprotectant causes the concern of people again.
Disease incidence or the death rate caused by can effectively reducing ionising radiation using radioprotectant.At present, clinically for spoke
It is more to penetrate the drug of protection, mainly there is sulfur-containing compound, estrogen, cytokine class etc., but has certain side effect mostly,
And druggability is poor, administration is inconvenient.
In order to overcome the shortcomings of more than drug, we, which design, has synthesized a series of 2,2- dimethylthiazoles alkyl compounds,
And radiation protection biological value and protection hematopoiesis, the experiment of immune system are carried out to it.
The content of the invention
1. a kind of compound of Formulas I
Wherein R can be C1-C6Straight chain and the preferred pi-allyl of the undersaturated alkyl substituent of branch, isopentene group, butyl- 2-
Alkenyl or aromatic radical or the preferred benzyl of substituted aromatic group and the benzyl of substitution, can also be C1-C6Straight chain and branch
Chain carbonyl substituent group, wherein the carbonyl substituent group can also be by the substituent groups containing heteroaromatic, and amino acid, halogen containing sulfydryl take
Generation.
2. the synthetic method of compound of formula I
By X and 2,2- dimethylthiazoles alkane occurs necleophilic reaction and is made.X can be C1-C6Straight chain and branch unsaturation alkane
Chloro thing, bromo-derivative, sulfuric ester, sulphonic acid ester or the benzyl of base and the chloro thing of substituted benzyl, bromo-derivative, sulfuric ester,
Sulphonic acid ester, preferably pi-allyl, isopentene group, but-2-ene base, benzyl, the chloro thing to methylbenzyl, bromo-derivative, sulfuric ester and
Sulphonic acid ester can also be C1-C6Straight chain and branch carbonyls such as acyl chlorides, acylbromide, acid anhydrides, ester and carboxylic acid, the wherein carbonylation
Closing object can also be further by the substituent group containing heteroaromatic, the amino acid containing sulfydryl, halogen substitution.
3. the pharmaceutically acceptable salt of compound of formula I falls within the scope of the present invention, pharmaceutically acceptable salt is
Hydrochloride, sulfate, tartrate or citrate.
4. it is another object of the present invention to disclose compound of formula I in protection hematopoiesis, immune system and radiation protection
In purposes.
The compound of the present invention can be prepared according to following scheme
X is Br, Cl ,-OSO3H、-SO2OR
Biological activity test
One, is to mouse hemopoietic, immune system Protection
Drug 1- 1. (2,2- dimethyl -3- thiazolidinyls) -2- [2- (5- methoxyl group -3- indyls) ethylamino-] ethyl ketone
(number is (number is compound 1), 2- amino -3- [2- (2,2- dimethyl -3- thiazolidinyls) -2- oxo second sulfydryl] propionic acid
Compound 2), 3- pi-allyl -2,2- dimethylthiazoles alkane (number is compound 3), 2,2- dimethyl -3- (3- methyl but-2-enes
Base) thiazolidine (number is compound 4), positive control drug be Amifostine.
The dosage of 1 each compound of table
2. the ICR mouse of SPF grades of barrier system raisings of animal, 6~7 week old, 20 ± 2g of weight.It is placed in the modeling of dry cleansing
Expect in cage tool, the raising of standard experimental animal feed, feed of freely intaking.
3. the condition of irradiation137The disposable full-body exposure of Cs gamma-rays, exposure dose rate 0.75Gy/min, mouse irradiation agent
It measures as 7.0Gy.
4. EXPERIMENTAL METHODS Animals are grouped at random, half male and half female, every group 10.Experiment sets blank control group, positive controls
And high, medium and low three dosage groups of compound 1 to 4.Pre-irradiation continuous 3 administrations on the the 3rd, 2,1, compound 1 and compound
2 gastric infusions, 4 intraperitoneal injection of compound 3 and compound.Blank control group gives physiological saline, before positive controls are shone
(dosage 250mg/kg) is administered in 30min once abdominal cavity injections.
5. the 7th day cervical dislocation of observation index puts to death mouse, observation leukocyte count (WBC), bonemarrow nucleated cells number
(BMNC), Spleen nodes number (CFU-S), bone DNA content, spleen index and thymus index.
6. result
2 compound 1 of table is to irradiated mice increasing leukocyte and hematopoiesis function protection test result
Note：The * P ＜ 0.01**P ＜ 0.001 compared with blank control group
3 compound 2 of table is to irradiated mice increasing leukocyte and hematopoiesis function protection test result
Note：The * P ＜ 0.01**P ＜ 0.001 compared with blank control group
4 compound 3 of table is to irradiated mice increasing leukocyte and hematopoiesis function protection test result
Note：The * P ＜ 0.01**P ＜ 0.001 compared with blank control group
5 compound 4 of table is to irradiated mice increasing leukocyte and hematopoiesis function protection test result
Note：The * P ＜ 0.01**P ＜ 0.001 compared with blank control group
The result shows that compound 1, in dosage 300mg/kg, BMNC, CFU-S have significantly compared with blank control group
Sex differernce, thymus index have extremely significant difference compared with blank control group；Compound 2 is in dosage 250mg/kg
BMNC, DNA content, CFU-S have significant difference, spleen index and thymus index and blank control group phase compared with blank control group
Than there is extremely significant difference；Compound 3 BMNC, spleen index in dosage 75mg/kg have aobvious compared with blank control group
Sex differernce is write, thymus index has extremely significant difference compared with blank control group；Compound 4 is in dosage 100mg/kg
CFU-S, spleen index, thymus index have significant difference compared with blank control group, and in the dosage of 50mg/kg, DNA contains
Amount, spleen index, thymus index also have significant difference compared with blank control group.It can be seen that compound 1-4 has protection mouse
Hematopoiesis and the effect of immune system.
Two, radiation protection are tested
1. experimental animal and grouping：The ICR mouse of SPF grades of barrier system raisings, 6~7 week old, 20 ± 2g of weight.It is placed in
In the plastics cage tool of dry cleansing, the raising of standard experimental animal feed, feed of freely intaking.Animal is grouped at random, half male and half female,
Every group 12, experiment sets false irradiation group, the administration group of irradiation group, positive controls (Amifostine) and compound 1 to 4 merely.
2. dosage and mode
Administering mode：Compound 1,2 gastric infusion of compound, compound 3,4 intraperitoneal injection of compound.
Dosage：For 300mg/kg, compound 3, compound 4 give medicament for compound 1, the dosage of compound 2
It measures as 80mg/kg.
3. the condition of irradiation：
137The disposable full-body exposure of Cs gamma-rays, exposure dose rate 0.75Gy/min, mouse exposure dose are 8.0Gy.
4. experiment flow
Pre-irradiation continuous 3 administrations on the the 3rd, 2,1, are injected intraperitoneally 0.1ml/10g, gastric infusion 0.25ml/10g.Vacation is shone
Group and simple irradiation group give physiological saline, and (dosage 250mg/ is administered according to preceding 30min once abdominal cavity injections in positive controls
Kg), treatment group is administered according to respective dosage and administering mode, is raised 30 days after irradiation and observes its time-to-live.
5. result
30 days different compound group survival rates and protective index after the irradiation of 6 mouse 8.0Gy gamma-rays of table
The result shows that compound 2 and compound 3 can be obviously prolonged by the life span according to mouse, there is radiation protection to make
With.
Embodiment
The present invention will be described in further detail by the following example, this is not limitation of the present invention.
Embodiment one：2- chloros -1- (2,2- dimethyl -3- thiazolidinyls) ethyl ketone
It weighs 2,2- dimethylthiazole alkane 10mmol to be dissolved in 10ml acetone, suitable anhydrous acetic acid is added under stirring at normal temperature
Sodium, the diluted 12mmol chloracetyl chlorides of dropwise addition acetone, react 2h under conditions of ice bath after being added dropwise, then gradually heating
To 40 DEG C of the reaction was continued 2h.Treat that removing solvent with Rotary Evaporators rotation after reaction obtains pink powder, adds in suitable CHCl3
Dissolving, washes through washing, Diluted Acid Washing, diluted alkaline and washes to obtain lurid CHCl with salt3Solution, rotation is except CHCl3Solvent obtains crude product.Slightly
Product (60~90 DEG C) of petroleum ether recrystallization, product are the acicular crystal of white, yield 89.2%.Mp66.2~67.8
℃.MS：Calculated value [C7H12NOSCl]+：193.5, test value [C7H12NOSCl]+：193.1.1H-NMR(300MHz CDCl3)δ
ppm：4.02 (s, 2H), 3.96 (t, 2H), 3.04 (t, 2H), 1.83 (s, 6H).
Embodiment two：2- amino -3- [2- (2,2- dimethyl -3- thiazolidinyls) -2- oxo second sulfydryl] propionic acid
L-cysteine 12mmol is added in 100ml reaction bulbs, with 3mol/LNH4After OH 15ml dissolvings, ice bath control
The 10mmol 2- chloros -1- (2,2- bis- for being dissolved in 10mL absolute ethyl alcohols is added dropwise in the case where being vigorously stirred to less than 3 DEG C for temperature
First -3- thiazolidinyls) ethyl ketone, maintain reaction temperature the reaction was continued 4h.Then solvent under reduced pressure is evaporated (＜ 40 with Rotary Evaporators
DEG C), obtain white solid, ethyl alcohol washing, filtering.Gained crude product H2O/C2H5OH is recrystallized, and obtains white needle crystals, is produced
Rate is 74.2%.178.3~179.7 DEG C of mp.MS：Calculated value [C10H18N2O3S2+H]+：279.0832, test value
[C10H18N2O3S2+H]+：279.0830.1H-NMR (300MHz, D2O)δppm：3.83 (m, 2H), 3.74 (m, 1H), 3.42 (s,
2H), 2.96 (m, 4H), 1.62 (s, 6H).IR：2977、2909(vas、vs CH3), 1632 (vasC=O), 3273,964 (v, γ
OH), 3369,1522 (v, δ NH2)。
Embodiment three：1- (2,2- dimethyl -3- thiazolidinyls) -2- [2- (5- methoxyl group -3- indyls) ethylamino-] second
Ketone
5.25mmol 5- methoxytryptamines are weighed to be dissolved in 20ml THF, add in suitable catalyst KI and
6mmolK2CO3, then 40 DEG C of stirring and dissolvings are added dropwise and are dissolved in 5mmol 2- chloros -1- (2, the 2- dimethyl -3- thiophenes of 10ml THF
Oxazolidinyl) ethyl ketone, 70 DEG C of back flow reaction 6h.It treats that solvent rotation is removed to obtain grey powder with Rotary Evaporators after reaction, adds in
Appropriate CHCl3Dissolving, washing, rotation is except CHCl3And appropriate 40 DEG C of stirrings of ethyl acetate are added in, filter to obtain gray solid, filter cake difference
It is washed with water and ethyl acetate.Gained crude product is recrystallized in acetone, obtains field gray flat crystal, yield 58.4%.
166.8~168.5 DEG C of mp.MS：Calculated value [C18H25N3O2S]+：347, test value [C18H25N3O2S]+：347.1H-NMR
(300MHz, CDCl3)δppm：8.11 (s, 1H), 7.24-6.08 (m, 4H), 3.85 (s, 3H), 3.75 (t, 2H), 3.35 (s,
2H), 2.96 (m, 6H), 1.98 (s, 1H), 1.82 (s, 6H).IR：2970、2886(vas、vs-CH3), 1655 (vasC=O),
3298th, 1488,1445 (v Indole), 3414,1583 (v, δ NH-).
Example IV：3- pi-allyl -2,2- dimethylthiazole alkane
It weighs 2,2- dimethylthiazole alkane 30mmol to be dissolved in 15ml acetone, proper catalyst is added under 40 DEG C of heating stirrings
The 36mmol allyl bromide, bromoallylenes after being diluted with 5ml acetone are slowly added dropwise in KI, 70 DEG C of back flow reaction 8h after being added dropwise.Filtering, filter cake
It is washed with ethyl acetate, it is dry.Crude product flows back in excessive propanone, filters to obtain white solid product, yield 78.4%.mp
184.8~186.3 DEG C.MS：Calculated value [C8H15NS]+：157, measured value [C8H15NS]+：157.1.1H-NMR (300MHz,
DMSO-d6)δppm：6.02 (m, 1H), 5.50 (m, 2H), 3.62 (t, 2H), 3.20 (t, 2H) (300MHz, DMSO-d6) δ ppm：
6.02 (m, 1H), 5.50 (m, 2H), 3.62 (t, 2H), 3.20 (t, 2H) 1.69 (d, 6H).
Embodiment five：2,2- dimethyl -3- (3- methyl but-2-enes base) thiazolidine
It weighs 2,2- dimethylthiazole alkane 30mmol to be dissolved in 15ml acetone, appropriate LI is added at 40 DEG C, then slowly drip
Add with the diluted 36mmol isoprenyl bromides of 5ml acetone, 70 DEG C of back flow reaction 8h.Filtering, filter cake are washed with ethyl acetate, are done
It is dry.Crude product flows back in excessive propanone, filters to obtain white solid product, yield 81.6%.182.2~183.7 DEG C of mp.
MS：Calculated value [C10H19NS]+：185, measured value [C10H19NS]+：185.1.1H-NMR (300MHz, DMSO-d6) δ ppm：5.36
(m, 1H), 3.90 (d, 2H), 3.55 (m, 2H), 3.18 (m, 2H), 1.72 (m, 12H).IR：2966、2916(vas、vs-CH3),
3000th, 1671,840 (v=C-HvC=Cγ=C-H), 2966 (vas-CH2-), 1196 (v-C-N-).
Claims (4)
1. a kind of compound with Formulas I structure
It is selected from：
(1) 3- pi-allyls -2,2- dimethylthiazole alkane
(3) 2,2- dimethyl -3- (3- methyl but-2-enes base) thiazolidine
(6) 2- amino -3- [2- (2,2- dimethyl -3- thiazolidinyls) -2- oxo second sulfydryl] propionic acid
(8) 1- (2,2- dimethyl -3- thiazolidinyls) -2- [2- (5- methoxyl group -3- indyls) ethylamino-] ethyl ketone.
2. the pharmaceutically acceptable salt of compound described in claim 1, which is characterized in that its pharmaceutically acceptable salt is salt
Hydrochlorate, sulfate, tartrate or citrate.
3. a kind of purposes of compound as described in claim 1 is used to prepare protection hematopoiesis function and the drug of immune system.
4. a kind of purposes of compound as described in claim 1, is used to prepare radioprotector.
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| CN201210414512.3A CN103772311B (en) | 2012-10-26 | 2, the 2- dimethylthiazoles alkyl compound and its preparation method and purposes of substitution |
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| CN201210414512.3A CN103772311B (en) | 2012-10-26 | 2, the 2- dimethylthiazoles alkyl compound and its preparation method and purposes of substitution |
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| CN103772311B true CN103772311B (en) | 2018-06-01 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3959304A (en) * | 1974-07-01 | 1976-05-25 | Stauffer Chemical Company | Certain 3-haloacyl-2,2,5-trimethyl-oxazolidines |
| JP2002193710A (en) * | 2000-12-25 | 2002-07-10 | Kumiai Chem Ind Co Ltd | Pyrimidine or triazine derivative and fungicide for agriculture and horticulture |
| CN101248054A (en) * | 2005-05-24 | 2008-08-20 | 雪兰诺实验室有限公司 | Thiazole derivatives and use thereof |
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3959304A (en) * | 1974-07-01 | 1976-05-25 | Stauffer Chemical Company | Certain 3-haloacyl-2,2,5-trimethyl-oxazolidines |
| JP2002193710A (en) * | 2000-12-25 | 2002-07-10 | Kumiai Chem Ind Co Ltd | Pyrimidine or triazine derivative and fungicide for agriculture and horticulture |
| CN101248054A (en) * | 2005-05-24 | 2008-08-20 | 雪兰诺实验室有限公司 | Thiazole derivatives and use thereof |
Non-Patent Citations (6)
| Title |
|---|
| Potential antiradiation agents. Preparation and polymerization of monomeric thiazolidines;Overberger C.G.等;《Journal of Medicinal Chemistry》;196511;第8卷(第6期);862-864 * |
| Reaction products of primary β-hydroxy amines with carbonyl compounds. XIII. Condensation of primary β-mercapto amines with carbonyl compounds;Ernst D, Bergmann等;《RECUEIL》;1959;第78卷;289-314 * |
| Synthesis of 2-alkyl- and 2-arylthiazolidines with or without substituent on the nitrogen atom;Tondeur Rene等;《Bulletin de la Societe Chimique de France》;1964(第10期);2493-2499 * |
| 噻唑烷类化合物的合成及其化学结构与辐射防护作用相互关系的研究;胡璧等;《中国医学科学院学报》;198502;第7卷(第1期);6-13 * |
| 四氢噻唑类(Thiazoliaines)和氨基烃代硫酸类(Aminoalkylthiosulfuric acid)作为抵抗电离辐射保护剂;A. Kaluszyner等;《南药译丛》;1961(第Z1期);106-107 * |
| 辐射防护剂2，2-二甲基四氢噻唑盐酸盐的研究_;宋小英等;《中国医学科学院学报》;197912;第1卷(第2期);147-153 * |
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